T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-κB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-κB as one of the major mediators of Notch1-induced transformation and suggest that the NF-κB pathway is a potential target of future therapies of T-ALL.
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We thank R. Duggan, J. Marvin, V. Bindokas, C. Labno, S. Li, J. Theusch and H. McDonald for technical support. W. Pear (University of Pennsylvania) provided the DN-MAML1 vector; C. Borowski (Harvard Medical School) provided the IkBαDN vector; and C. Gelinas (Cancer Institute of New Jersey) provided the Ikbka (IKKβSS-EE) retroviral plasmid. We also acknowledge A. Montag for interpretation of histological samples. I.A. is supported by the Sidney Kimmel Foundation for Cancer Research, the G&P Foundation for Cancer Research and by US National Institutes of Health grant R01CA105129. L.M. is supported by National Institutes of Health grants R01CA84065 and P01AG025531. B.L.K. is supported by the Concern Foundation and the Leukemia Research Foundation.
The authors declare no competing financial interests.
Expression of Notch1-IC in bone marrow lineage-negative progenitors results in activation of a T lineage transcriptional program and down-regulation of myeloid and B cell genes. (PDF 403 kb)
Gene expression and proliferation of Ptcra−/− Notch1-IC+ bone marrow progenitors is comparable to that of wt-Notch1-IC+ progenitors. (PDF 158 kb)
γ-secretase inhibitors block NF-γB activation in KOPTK1 T-ALL cells. (PDF 429 kb)
Effects of γ-secretase inhibitors on NF-κB activation and growth of T-ALL cell lines. (PDF 266 kb)
Active, mutated Notch1 interacts with the IKK complex in KOPTK1 T-ALL cells. (PDF 109 kb)
Activation of the NF-κB pathway in human T-ALL lines harboring activating Notch1 mutations. (PDF 403 kb)
Notch1-IC activates a T lineage transcriptional profile and suppresses expression of B cell and myeloid-specific genes in bone marrow progenitors (PDF 41 kb)
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Vilimas, T., Mascarenhas, J., Palomero, T. et al. Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13, 70–77 (2007). https://doi.org/10.1038/nm1524
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